Drug-related side effects and adverse reactions

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Drug-related side effects and adverse reactions, also called adverse drug reaction (ADR), adverse drug event (ADE) or drug toxicity, is defined as the "manifestations of the adverse effects of drugs administered therapeutically or in the course of diagnostic techniques. It does not include accidental or intentional poisoning..."[1] The meaning of this expression differs from the meaning of "side effect", as this last expression might also imply that the effects can be beneficial.[2]

The World Health Organization defines it as:

An adverse drug reaction (ADR) is ‘a response to a medicine which is

noxious and unintended, and which occurs at doses normally used in man’. In this description it is of importance that it concerns the response of a patient, in which individual factors may play an important role, and that the phenomenon is noxious (an unexpected therapeutic

response, for example, may be a side effect but not an adverse reaction).[3]

6% of hospital admissions[4] and 2.5% of emergency department visits for injuries or poisonings[5] may be due to adverse drug reactions. Adverse drug reactions also occur among ambulatory outpatients[6] and among inpatients[7]. A minority of drug toxicity is recognized by health care providers.[8]



The World Health Organization (WHO) classifies ADRs by cause:[9]

  • Type A: Dose-related; pharmacologically predictable. In a study of older adults, this type was the most common with the most common offending drugs being warfarin, insulin, and digoxin.[10]
  • Type B: Non-dose related; bizarre and unpredictable.
  • Type C: Dose-related and time-related. This is related to duration and dosage of exposure. An example is hypothalamic-pituitary-adrenal suppression from glucocorticoid therapy.
  • Type D: Time-related; delayed reaction. An example is tardive dyskinesia.
  • Type E: Withdrawal; end of dose reaction. An example is narcotic or beta-blocker withdrawal.
  • Type F: Unexpected failure of therapy. This may be caused by drug interactions. An example is failure of oral contraceptives due to induction of enzymes by a second drug.

Types A and B were proposed in the 1970s,[11] and the other types were proposed subsequently when the first two proved insufficient to classify ADRs.[12]


Immediate hypersensitivity

Immediate hypersensitivity are over-reported and few patient reporting these have reactions on careful testing.[13][14]

Drug-induced liver injury

For more information, see: Drug-induced liver injury.

Drug reaction with eosinophilia and systemic symptoms

Drug reaction with eosinophilia and systemic symptoms (DRESS) may be caused by medications including allopurinol, phenytoin, dapsone, carbamazepine, trimethoprim-sulfamethoxazole, penicillin, and non-steroidal anti-inflammatory agents.[15] About half of cases have eosinophilia.

Drug-drug interactions

Some interactions are due to the system of cytochrome P-450 enzymes used to clear drugs from the body. These interactions can be complex, involving either increasing or decreasing the activity of a given cytochrome pathway, or preferentially (i.e., competitive inhibition) using the pathway rather than other drugs. As one example, theophylline and ciprofloxacin up-regulate the cytochrome pathway that also clears estrogen and phenytoin. As a result, oral contraceptives and anticonvulsants may fail because the pathway clears them too quickly and an adequate blood level cannot be maintained.

Drug-disease interactions

Drug-food interactions

Monoamine oxidase inhibitors can cause fatal hypertension in patients who have also consumed food containing high concentrations of tyramine. The suspect foods form an odd assortment, such as Chianti wine, some smoked fish and aged cheese.

QT interval prolongation

For more information, see: QT interval.


Hyperpigmentation may occur due to drug toxicity.[16][17]


For more information, see: Thombocytopenia.

Describing ADRs

ADRs may be described by their frequency and severity


The World Health Organization recommends standardization of descriptions of frequency.[18] Although the WHO document is not currently available online, their recommendations have been summarized by others.[19]

  • very common (>1/10 patients)
  • common (>1/100)
  • uncommon (>1/1000)
  • rare (>1/10,000)
  • very rare (<1/100,000)


The American Food and Drug Administration defines severe effects as:[20]:

  • Death
  • Life-Threatening
  • Hospitalization (initial or prolonged)
  • Disability - significant, persistent, or permanent change, impairment, damage or disruption in the patient's body function/structure, physical activities or quality of life.
  • Congenital Anomaly
  • - or -
  • Requires Intervention to Prevent Permanent Impairment or Damage

Etiology / cause

As research better explains the biochemistry of drug use, less ADRs are Type B ('idiosyncratic') and more are Type A (pharmacologically predictable). Common mechanisms are:

  • Abnormal pharmacokinetics due to
    • genetic factors
    • comorbid disease states
  • Synergistic effects between either
    • a drug and a disease
    • two drugs

Risk factors are:[21]

  • The number of drugs
  • History of prior drug toxicity
  • Presence of heart failure
  • Presence of liver disease
  • Presence of renal failure
  • Presence of 4 or more medical conditions

Abnormal pharmacokinetics

Comorbid disease states

Various diseases, especially those that cause renal or hepatic insufficiency, may alter drug metabolism. Resources are available that report changes in a drug's metabolism due to disease states.[22] However, heavy physician workload may reduce the ability of the physician to use these resources.[23]

Genetic factors

For more information, see: Pharmacogenomics.

Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation.[24][25] Pharmacogenomics is the study on the inherited basis of drug reactions. Among drugs frequently cited in adverse drug reactions, 60% are metabolized by enzymes with genetic variations in metabolism. 7% to 22% of randomly selected have such variation.[24]

Phase I reactions

Inheriting abnormal alleles of cytochrome P-450 can alter drug metabolism. Tables are available to check for drug interactions due to cytochrome P-450 interactions.[26].[27]

Inheriting abnormal butyrylcholinesterase (pseudocholinesterase) may affect metabolism of drugs such as succinylcholine[28]

Phase II reactions

Inheriting abnormal N-acetyltransferase which conjugated some drugs to facilitate excretion may affect the metabolism of drugs such as isoniazid, hydralazine, and procainamide.[28][27]

Inheriting abnormal thiopurine S-methyltransferase may affect the metabolism of the thiopurine drugs mercaptopurine and azathioprine.[27]

Impaired hepatic function

Food and Drug Administration provides guidance on the labeling of prescription medications to guide dosing for patients with impaired hepatic function.[29]

Impaired renal function

Food and Drug Administration categories of renal function[30]
Group Description Estimated creatinine clearance (ml/min)
1 Normal renal function > 80 mL/min
2 Mild renal function > 50-80 mL/min
3 Moderate renal function > 30-50 mL/min
4 Severe renal function <30 mL/min
5 ESRD Requiring dialysis

The National Kidney Disease Education Program provides guidance on dosing drugs in patients with reduced glomerular filtration rate.[31] Food and Drug Administration provides guidance on the labeling of prescription medications to guide dosing for patients with impaired renal function.[30] Although this categorization uses estimated creatinine clearance, using estimated glomerular filtration yields similar recommendations for dosing adjustments.[32]

Interactions with other drugs

For more information, see: Drug interaction.

Synergistic effects

An example of synergism is two drugs that both prolong the cardiac QT interval.

Other factors that my increase ADRs


For more information, see: polypharmacy.

The risk of drug interactions may be increased with polypharmacy. Using 11 or more chronic medications is a risk factor for drug toxicity.[33]

Fragmented health care

When controlled for other factors such as the number of prescribing physicians, the number of medicatations may not be a risk factor for adverse drug reactions.[34]

Assessing causality

A scale proposed by the World Health Organization (WHO) is below:[35][9][2]


  • "A clinical event, including a laboratory test abnormality, that occurs in a plausible time relation to drug administration, and which cannot be explained by concurrent disease or other drugs or chemicals"
  • "The response to withdrawal of the drug (dechallenge) should be clinically plausible"
  • "The event must be definitive pharmacologically or phenomenologically, using a satisfactory rechallenge procedure if necessary"


  • "A clinical event, including a laboratory test abnormality, with a reasonable time relation to administration of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, and which follows a clinically reasonable response on withdrawal (dechallenge)"
  • "Rechallenge information is not required to fulfil this definition"


  • "A clinical event, including a laboratory test abnormality, with a reasonable time relation to administration of the drug, but which could also be explained by concurrent disease or other drugs or chemicals"
  • "Information on drug withdrawal may be lacking or unclear"


  • "A clinical event, including a laboratory test abnormality, with a temporal relation to administration of the drug, which makes a causal relation improbable, and in which other drugs, chemicals, or underlying disease provide plausible explanations"


  • "A clinical event, including a laboratory test abnormality, reported as an adverse reaction, about which more data are essential for a proper assessment or the additional data are being examined"


  • "A report suggesting an adverse reaction that cannot be judged, because information is insufficient or contradictory and cannot be supplemented or verified"

An alternative scale is the Naranjo algorithm.

Intolerance to multiple drugs

Amplification may contribute to multiple-drug intolerance (if the adverse effects that are reported are non-specific).[36] This is distinct from multiple drug hypersensitivity.[37]

In the emergency department, clinical prediction rules are available to identify drug toxicity.[38]

Detection of toxicity in individual patients

The question "In the past XX months, have you noticed any side effects, unwanted reactions, or other problems with medications you have taken?" may help detect toxic reactions.[39]

Detection of previously unrecognized toxicity in populations

Unfortunately, more drug toxicity is not reported.[40][41][42] Reports of more than three cases of a rare disease associated with a drug suggests the drug may be causing the disease.[43] More complicated rules for signals are available.[44]

Scientific journals

News of previously unrecognized drug toxicity may be first published in scientific journals. Published reports may be more helpful than spontaneous reports[45] although drug toxicity is more likely to be spontaneously reported than published[46]. However, published reports may be lacking in quality.[47]

Search strategies of MEDLINE are available.[48]

Monitoring bodies

Many countries have official bodies that monitor drug safety and reactions. On an international level, the World Health Organization (WHO) runs the Uppsala Monitoring Centre, and the European Union runs the European Medicines Agency (EMEA). In the United States of America, the Food and Drug Administration (FDA) is responsible for monitoring post-marketing studies. However, the book, Physicians' Desk Reference, which is a collection of FDA approved drug labels, may contribute to adverse drug effects by systematically underreporting the lowest effect dose of drugs.[49]


Computerized provider order entry

The role of computerized provider order entry (CPOE) may prevent ADRs according to a systematic review.[50] However, individual studies have been inconsistent with both positive[51][52][53] and negative[54] effects on process measures. CPOE has difficulty in precision of alerting.[55]

Non-physicians may be able to successfully use CPOE.[56]

Overriding of alerts may decrease patient safety.[57]

Medication reconciliation

Medication reconciliation may help.[58]

Lists of high risk medications

The Beers list has been developed for predictable adverse drug reactions and thus provide a list of medications to avoid.[59] After the original list of medications was not associated with clinical outcomes[60], the list is periodically revised with a Delphi method.[61][62] The current list is online. The Beers list has become a clinical measure of quality assurance.[63]

The STOPP and START Criteria criteria may be better.[64][65]

Genetic screening

For more information, see: Pharmacogenomics.

Screening for HLA-B*5701 may reduce the incidence of hypersensitivity reactions to abacavir according to a randomized controlled trial.[66]


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